OCULAR DRUG DELIVERY SYSTEMS

-By K .VijayalakshmiM.Pharm (1st year)

INTRODUCTION Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases.

Eye is the most easily accessible site for topical administration of a medication.

Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain in the vicinity of front of the eye for prolong period of time.

COMPOSITION OF EYE:

Water - 98%, Solid -1.8%, Organic element – Protein -

0.67%, sugar - 0.65%, NaCl - 0.66%

Other mineral element sodium, potassium and

ammonia - 0.79%.

EYE AND LACRIMAL DRAINAGE SYSTEM

ANATOMY OF EYE:

ROUTES OF DRUG DELIVERY IN EYE

MECHANISM OF OCULAR ABSORPTION

Non- corneal absorption:Penetration across sclera & conjunctiva into intra ocular tissues.Non productive: because penetrated drug is absorbed by general circulation.Corneal absorption:Outer epithelium: rate limiting barrier, with pore size 60a, only access to small ionic and lipophilic molecules.Trans cellular transport: transport between corneal epithelium and stroma.

FACTORS AFFECTING INTRAOCULAR BIOAVAILABILITY:1. Inflow & outflow of lacrimal fluids.2. Efficient naso-lacrimal drainage.3. Interaction of drug with proteins of lacrimal fluid.4. dilution with tears.5. Corneal barriers.6. Active ion transport at cornea.

BARRIERS AVOIDING DRUG DELIVERY

Drug in tear fluid

Ocular absorption

Corneal route Conjunctival and scleral route Systemic absorption 50-100% of dose Major route- conjunctiva of eye, nose Minor route- lacrimal drainage system, pharynx, GIT, aqueous humor

Aqueous humor

Ocular tissue ELIMINATION

OPHTHALMIC DOSAGE FORM Ophthalmic preparations are sterile products essentially free from foreign particles, suitably compounded and packaged for instillation in to the eye. The following dosage forms have been developed to ophthalmic drugs. Some are in common use, some are merely experimental, and others are no longer used.

OCULAR DELIVERY SYSTEMS

CONVENTIONAL VESICULAR

CONTROL RELEASE

PARTICULATE

SOLUTIONSUSPENTIONEMULSIONOINTMENTINSERTGELS

IMPLANTSHYDROGELSDENDRIMERS

IONTOPORESISCOLLAGEN SHIELD

POLYMERIC SOLUTIONS

CONTACT LENSESCYCLODEXRIN

MICROONEEDLEMICROEMULSIONSNANO SUSPENSION

ADVANCED

SCLERAL PLUGSGENE DELIVERYSi RNASTEM CELLECT

MICROPARTICLESNANOPARTICLES

LIPOSOMESNIOSOMESDISCOMESPHARMACOSOMES

SELECTED TYPES OF OCDDS:

1. Aqueous eye drops 2. Oily eye drops

3. Eye ointments 4. Eye lotions

5. Paper strips 6. Ocuserts 7. Hydro gel contact lenses 8. Collagen shields 9. Ophthalmic rods

ADVANTAGES: They are easily administered by the nurse They are easily administered by the patient himself. They have the quick absorption and effect. less visual and systemic side effects. increased shelf life. better patient compliance.

DISADVANTAGES: The very short time the solution stays at the eye surface.

Its poor bioavailability.

The instability of the dissolved drug. The necessity of using preservative.

IDEAL CHARACTERISTICS OF OCDDS:

SterilityIsotonicity-e.g.: 1.9% boric acid, 0.9% NaClBuffer/pH adjustmentLess drainage tendencyMinimum protein binding

FORMULATION OF OCULAR DRUG DELIVERY SYSTEM:

Dosage Form

Advantages Disadvantages

solutions convenience Rapid precorneal elimination, non sustained action

suspension Patient compliance, best for drug with slow dissolution

Drug properties decide performance loss of both solutions and suspended particles

emulsion Prolonged release of drug from vehicle

Blurred vision, patient non compliance

ointment Flexibility in drug choice, improved drug stability

Sticking of eyes lids, blurred vision, poor patient compliance

RECENT FORMULATION TRENDS IN OCDDS:1. CONVENTIONAL DELIVERY

SYSTEMS:

Eye Drops:Drugs which are active at eye or eye surface are widely administered in the form of Solutions, Emulsion and Suspension.Various properties of eye drops like hydrogen ion concentration, osmolality, viscosity and instilled volume can influence retention of a solution in the eye. Less than 5 % of the dose is absorbed after topical administration into the eye.The dose is mostly absorbed to the systemic blood circulation via the conjunctival and nasal blood vessels.

Ointment and Gels: Prolongation of drug contact time with the external ocular surface can be achieved using ophthalmic ointment vehicle but, the major drawback of this dosage form like, blurring of vision & matting of eyelids can limit its use.

Ocuserts and Lacrisert: Ocular insert (Ocusert) are sterile preparation that prolong residence time of drug with a controlled release manner and negligible or less affected by nasolacrimal damage. Inserts are available in different varieties depending upon their composition and applications. Lacrisert is a sterile rod shaped device for the treatment of dry eye syndrome and keratitis sicca.They act by imbibing water from the cornea and conjunctiva and form a hydrophilic film which lubricates the cornea.

2) VESICULAR SYSTEM: Liposomes:

Liposomes are biocompatible and biodegradable lipid vesicles made up of natural lipids and about 25–10 000 nm in diameter. They are having an intimate contact with the corneal and conjunctival surfaces which is desirable for drugs that are poorly absorbed, the drugs with low partition coefficient, poor solubility or those with medium to high molecular weights and thus increases the probability of ocular drug absorption. 

Niosomes and Discomes:The major limitations of liposomes are chemical instability, oxidative degradation of phospholipids, cost and purity of natural phospholipids. To avoid this niosomes are developed as they are chemically stable as compared to liposomes and can entrap both hydrophobic and hydrophilic drugs. They are non toxic and do not require special handling techniques.

Niosomes are nonionic surfactant vesicles that have potential applications in the delivery of hydrophobic or amphiphilic drugs.

Discomes may act as potential drug delivery carriers as they released drug in a sustained manner at the ocular site.Discosomes are giant niosomes (about 20 um size) containing poly-24- oxy ethylene cholesteryl ether or otherwise known as Solulan 24.

Pharmacosomes: This term is used for pure drug vesicles formed by the amphiphilic drugs.The amphiphilic prodrug is converted to pharmacosomes on dilution with water.

Niosomes are microscopic lamellar structures, which are formed on the admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media.Structurally, niosomes are similar to liposomes, in that they are also made up of a bilayer. However, the bilayer in the case of niosomes is made up of non-ionic surface active agents rather than phospholipids as seen in the case of liposomes.

Non ionic surface active agent

phospholipid

Hydrophilic drugs in aqueous region encapsulatedLipophilic drugs located in the hydrophobic lamella

NIOSOME Vs LIPOSOME

3) CONTROL DELIVERY SYSTEMS:1. Implants: For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implants are effective drug delivery system. Earlier non biodegradable polymers were used but they needed surgical procedures for insertion and removal. Presently biodegradable polymers such as Poly Lactic Acid (PLA) are safe and effective to deliver drugs in the vitreous cavity and show no toxic signs.2. Iontophoresis: In Iontophoresis direct current drives ions into cells or tissues. For iontophoresis the ions of importance should be charged molecules of the drug.Positively charged of drug are driven into the tissues at the anode and vice versa. Ocular iontophoresis delivery is not only fast, painless and safe but it can also deliver high concentration of the drug to a specific site.3. Dendrimer: Dendrimers can successfully used for different routes of drug administration and have better water-solubility, bioavailability and biocompatibility.

4. Microemulsion: Microemulsion is dispersion of water and oil stabilized

using surfactant and co- surfactant to reduce interfacial tension and usually characterized by small droplet size (100 nm), higher thermodynamic stability and clear appearance.

Selection of aqueous phase, organic phase and surfactant/co-surfactant systems are critical parameters which can affect stability of the system. 5. Nanosuspensions:

Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs because they enhanced not only the rate and extent of ophthalmic drug absorption but also the intensity of drug action with significant extended duration of drug effect.

For commercial preparation of nanosuspensions, techniques like media milling and high-pressure homogenization have been used.

6. Microneedle: Microneedle had shown prominent in vitro penetration

into sclera and rapid dissolution of coating solution after insertion while in vivo drug level was found to be significantly higher than the level observed following topical drug administration like pilocarpine.

7. Mucoadhesive Polymers: They are basically macromolecular hydrocolloids with

plentiful hydrophilic functional groups, such as hydroxyl, carboxyl, amide and sulphate having capability for establishing electrostatic interactions

A mucoadhesive drug formulation for the treatment of glaucoma was developed using a highly potent beta blocker drug, levobetaxolol (LB) hydrochloride and partially neutralized poly acrylic acid (PAA).

4) PARTICULATES (NANOPARTICLES AND MICROPARTICLES):

The maximum size limit for microparticles for ophthalmic administration is about 5-10 mm above which a scratching feeling in the eye can result upon ocular instillation. That is why microspheres and nanoparticles are promising drug carriers for ophthalmic application. Nanoparticles are prepared using bioadhesive polymers to provide sustained effect to the entrapped drugs.

INSERTS CLASSIFICATION :

1 .NON ERODIBLE INSERTSi. Ocusertii. Contact lens

2 .ERODIBLE INSERTSiii. Lacrisertsiv. SODIv. Mindisc

1) NON ERODIBLE INSERTSOCUSERT:

The Ocusert therapeutic system is a flat, flexible, elliptical device designed to be placed in the inferior cul-de-sac between the sclera and the eyelid and to release Pilocarpine continuously at a steady rate for 7 days.

The device consists of 3 layers…..1. Outer layer - ethylene vinyl acetate copolymer layer.2. Inner Core - Pilocarpine gelled with alginate main polymer.3. A retaining ring - of EVA impregnated with titanium di oxide (diagram)

The ocuserts available in two forms.Pilo - 20 :- 20 microgram/hourPilo – 40 :-40 micrograms/hour

ADVANTAGES:Reduced local side effects and toxicity.Around the clock control of IOP.Improved compliance.DISADVANTAGES:Retention in the eye for the full 7 days.Periodical check of unit.Replacement of contaminated unitExpensive.

CONTACT LENSES: These are circular shaped structures. Dyes may be added during polymerization. Drug incorporation depends on whether their structure

is hydrophilic or hydrophobic.Drug release depends upon : Amount of drug Soaking time. Drug concentration in soaking solution.

ADVANTAGES: No preservation. Size and shape

DISADVANTAGES: Handling and cleaning Expensive

2) ERODIBLE INSERTS:The solid inserts absorb the aqueous tear fluid and gradually erode or disintegrate. The drug is slowly leached from the hydrophilic matrix.they quickly lose their solid integrity and are squeezed out of the eye with eye movement and blinking.do not have to be removed at the end of their use.Three types :1. LACRISERTS2. SODI3. MINIDISC

LACRISERTS:Sterile rod shaped device made up of hydroxyl propyl cellulose without any preservative.For the treatment of dry eye syndromesIt weighs 5 mg and measures 1.27 mm in diameter with a length of 3.5 mm.It is inserted into the inferior fornix.

SODI:Soluble ocular drug insertsSmall oval waferSterile thin film of oval shapeWeighs 15-16 mgUse – glaucomaAdvantage – Single application 

MINIDISC: Countered disc with a convex front and a concave back surfaceDiameter – 4 to 5 mmComposition:Silicone based prepolymer-alpha-w-dis (4-methacryloxy)-butyl poly di methyl siloxane. (M2DX)M-Methyl a cryloxy butyl functionalities.D – Di methyl siloxane functionalities.Pilocarpine, chloramphenicol

EVALUATION OF OCDDS:

THICKNESS OF THE FILM:Measured by dial caliper at different points and the mean value is calculated.DRUG CONTENT UNIFORMITY:The cast film cut at different places and tested for drug as per monograph.UNIFORMITY OF WEIGHT:Here, three patches are weighed.

PERCENTAGE MOISTURE ABSORPTION:Here ocular films are weighed and placed in a dessicator containing 100 ml of saturated solution of aluminium chloride and 79.5% humidity was maintained.After three days the ocular films are reweighed and the percentage moisture absorbed is calculated using the formula =% moisture absorbed = Final weight – initial weight/ initial weight x 100

IN – VITRO EVALUATION METHODS: BOTTLE METHOD:In this, dosage forms are placed in the bottle containing dissolution medium maintained at specified temperature and pH.The bottle is then shaken.A sample of medium is taken out at appropriate intervals and analyzed for the drug content. DIFFUSION METHOD:Drug solution is placed in the donor compartment and buffer medium is placed in between donor and receptor compartment.Drug diffused in receptor compartment is measured at various time intervals.

MODIFIED ROTATING BASKET METHOD:Dosage form is placed in a basket assembly connected to a stirrer.The assembly is lowered into a jacketed beaker containing buffer medium and temperature 37 degrees Centigrade.Samples are taken at appropriate time intervals and analyzed for drug content. 

MODIFIED ROTATING PADDLE APPARATUS:Here, dosage form is placed into a diffusion cell which is placed in the flask of rotating paddle apparatus.The buffer medium is placed in the flask and paddle is rotated at 50 rpm.The entire unit is maintained at 37 degree C.Aliquots of sample are removed at appropriate time intervals and analyzed for drug content. 

IN- VIVO STUDY:Here, the dosage form is applied to one eye of animals and the other eye serves as control.

Then the dosage form is removed carefully at regular time interval and are analyzed for drug content.

The drug remaining is subtracted from the initial drug content, which will give the amount of the drug absorbed in the eye of animal at particular time.

After one week of washed period, the experiment was repeated for two time as before.

ACCELERATED STABILITY STUDIES:

These are carried out to predict the breakdown that may occur over prolonged periods of storage at normal shelf condition.Here, the dosage form is kept at elevated temperature or humidity or intensity of light, or oxygen.Then after regular intervals of time sample is taken and analyzed for drug content.From these results, graphical data treatment is plotted and shelf life and expiry date are determined.

CONCLUSION:All approaches improve ocular drug bioavailability by increasing ocular drug residence time, diminish side effects due to systemic absorption and diminishing the necessary therapeutic amount of drug for therapeutic response in anterior chamber.They improve patient compliance by reducing the frequency of dosing.They reduce the dose and thereby reduce the adverse effects of the drug.

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